We operate two clinical centers of Look AHEAD, a multicenter randomized clinical trial of weight loss for prevention of complications of type 2 diabetes. Since the clinical trial began in 2002, 5,145 volunteers with type 2 diabetes who were 45-76 years of age and overweight or obese (body mass index > 25 kg/m2) were enrolled in either the intensive lifestyle intervention (ILI) program or the diabetes support and education (DSE) program. The Diabetes Epidemiology and Clinical Research Section clinics enrolled 244 of these participants. The study has reported success in achieving and maintaining weight loss in the ILI group, while there was little weight loss on average in the DSE group. During the first four years after enrollment, the average weight losses were 6.2% in the ILI group and 0.9% in the DSE group. Effects of the weight loss on several health outcomes were reported in previous years. Several more health outcomes were reported during the current fiscal year. Cognitive function. Mild cognitive impairment and probable dementia were classified based on standardized cognitive test battery scores. At an average (range) of 11.4 (9.513.5) years after enrollment, when participants mean age was 69.6 (54.987.2) years, the prevalence of mild cognitive impairment and probable dementia was 6.4% and 1.8%, respectively, in the intervention group, compared with 6.6% and 1.8%, respectively, in the control group. The lack of an intervention effect on the prevalence of cognitive impairment was consistent among individuals grouped by cardiovascular disease history, diabetes duration, sex, and APOE e4 allele status. However, the intervention effect ranged from benefit to harm across participants ordered from lowest to highest baseline BMI. Ten years of behavioral weight loss intervention did not result in an overall difference in the prevalence of cognitive impairment among overweight or obese adults with type 2 diabetes. Risk of fractures. Intentional weight loss is an important treatment option for overweight persons with type 2 diabetes mellitus (DM), but the effects on long-term fracture risk were not known. There were no statistically significant differences in incident total or hip fracture rates between the ILI and DSE groups in Look AHEAD. However, compared to the DSE group, the ILI group had a statistically significant 39% increased risk of a frailty fracture (HR 1.39; 95% CI, 1.02 to 1.89). An intensive lifestyle intervention resulting in long-term weight loss in overweight/obese adults with DM was not associated with an overall increased risk of incident fracture but may be associated with an increased risk of frailty fracture. When intentional weight loss is planned, consideration of bone preservation and fracture prevention is warranted. A genetic predictor of cardiovascular disease. Genetic studies have identified a glutamate-ammonia ligase gene (GLUL) polymorphism associated with cardiovascular disease morbidity and mortality among people with type 2 diabetes (T2D). Over a median of 9.6 years of follow-up in Look AHEAD, the risk (C) allele for GLUL rs10911021 was significantly associated with the primary composite end point of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina among individuals with no history of cardiovascular disease (CVD) at baseline using additive genetic models (hazard ratio 1.17 95% CI 1.011.36; P = 0.032). Results appeared more consistent in recessive models and among individuals with no known history of CVD at baseline; ILI did not alter these associations. These results extend the association of GLUL rs10911021 to incident CVD morbidity and mortality in the setting of T2D. Diabetic neuropathy. We evaluated intervention effects on diabetic peripheral neuropathy (DPN). Neuropathy evaluations included the Michigan Neuropathy Screening Instrument (MNSI) questionnaire completed at baseline in 5145 participants (ILI n = 2570, DSE n = 2575) and repeated annually thereafter and the MNSI physical examination and light touch sensation testing conducted in 3775 participants (ILI n = 1905, DSE n = 1870) 12.3 years after discontinuation of the intervention. ILI resulted in a significant decrease in questionnaire-based DPN, which was associated with the magnitude of weight loss. In both the ILI and DSE groups, changes in the MNSI score were also related to changes in HbA1c and lipids. There were no significant effects of ILI on physical examination measures of DPN conducted 12.3 years after termination of the active intervention, except for light touch sensation, which was significantly better in the ILI group when measurements were combined for both toes. Costs of the lifestyle weight loss intervention. We described the cost of delivering the intensive lifestyle intervention (ILI) in the Look AHEAD clinical trial. The ILI, designed to promote weight loss and increase physical activity. involved a combination of group plus individual intervention sessions, with decreasing frequency of contact over the 10 years. The intervention incorporated a variety of strategies, including meal replacement products, to improve weight loss outcomes. The costs of intervention delivery were derived from staff surveys of effort and from records of intervention materials from the 16 US academic clinical trial sites. Costs were calculated from the payer perspective and presented in 2012 dollars. During the first year, when intervention delivery was most intensive, the annual cost of intervention delivery, averaged (standard deviation) across clinical sites, was $2,864.6 ($513.3) per ILI participant compared with $202.4 ($76.6) per DSE participant. As intervention intensity declined, costs decreased, such that from years 5 to 9 of the trial, the annual cost of intervention was $1,119.8 ($227.7) per ILI participant and $102.9 ($33.0) per DSE participant. Staffing accounted for the majority of costs throughout the trial, with meal replacements and materials to promote adherence accounting for smaller shares. The sustained weight losses produced by the Look AHEAD intervention were supported by intervention costs that were within the range of other weight loss programs. Future work will include an evaluation of the cost-effectiveness of the ILI and will contain additional follow-up data.